Psychostimulants, such as methylphenidate (MPH) and methamphetamine, are widely used and abused. The short-term adverse health effects of methamphetamine abuse are well known. Although much less is known about the long-term effects, changes in pain modulation appear to be a potentially important consequence. Our preliminary data show that chronic administration of MPH to young rats enhances morphine antinociception and facilitates the development of tolerance to morphine as adults. Behavioral and anatomical data suggest that dopamine, the neurotransmitter underlying the effects of psychostimulants, and opioids interact in the periaqueductal gray (PAG). The studies in this proposal focus on the PAG as a novel shared neurobiological substrate mediating changes in pain modulation associated with psychostimulant use. The ventrolateral PAG is critical for opioid analgesia and also contains intrinsic dopaminergic neurons that are a likely target of psychostimulant drugs. Thus, the PAG represents a site of convergence between dopamine and pain modulation. Changes in morphine antinociception and tolerance could be caused by changes in opioid potency or changes in basal pain states. This proposal uses a collaborative team science approach to examine PAG function at electrophysiological, anatomical, and behavioral levels. Experiments in Aim #1 will focus on changes in opioid tolerance, as well as opioid receptor potency and desensitization following psychostimulant administration. Experiments in Aim #2 will test the hypothesis that psychostimulants enhance chronic pain via changes in neural processing in the PAG. Finally, Aim #3 will test the hypothesis that combining chronic psychostimulant administration and chronic pain will produce unique interactions between dopamine and opioid systems in the PAG. These studies will clarify the cellular substrates for opioid/dopamine interactions in the PAG and how these cells fit into the central networks that underlie the long- term consequences of drug abuse on pain. We will test the overall hypothesis that the PAG is a critical substrate for the changes in nociception and analgesia produced by chronic psychostimulant use. The proposed studies will provide a better understanding of the cellular mechanisms that contribute to chronic pain in patients with a history of drug abuse so effective treatments can be developed. ) PUBLIC HEALTH RELEVANCE: Psychostimulants, including methylphenidate (MPH) and methamphetamine are commonly abused drugs that can enhance opioid analgesia. However, few studies have addressed the long-term consequences of psychostimulant use and abuse on endogenous pain pathways. Our preliminary data demonstrate that prior psychostimulant use increases the development of tolerance to opioids, potentially resulting in increased numbers of chronic pain patients resistant to opioid analgesics. Given the widespread use and abuse of psychostimulants, the potential long-term suffering from chronic pain and associated healthcare costs in this population are enormous. )